Hepatitis B Virus (HBV) has infected more than 2 billion people around the world and causes temporary and chronic liver diseases. Although a vaccine against HBV was introduced in 1982, globally 350 million people are infected chronically. The risk of chronic infection is correlated with patient's age at time of infection. Infection persists in about 90% of infants infected during the first year of life. In contrast, infection persists only in 1-5% of patients infected as adults.
Active replication of HBV is characterized by liver damage, most likely due to immune reactivity. Chronic HBV infection can lead to liver cancer and dead. About 25% of adults who become chronically infected during childhood die from HBV-related liver cirrhosis or cancer, an estimated 500,000 to 1.2 million persons each year.
The immune response to HBV consists of both a cellular immune response for the elimination of HBV infected cells, as well as a humoral antibody response, which contributes to the clearance of circulating virus particles. The major viral component responsible for the induction of neutralizing HBV antibodies is the small HBV surface antigen (HBsAg).
All recombinant vaccines contain HBsAg and the efficacy of these vaccines is high (protection in more than 95% of infants, children and young adults) and long lasting (>20 years). In addition, all vaccines elicit the immunity across serotypes. HBsAg consists of 226 amino acids, with one N-linked glycosylation site. Comparison of circulating HBV strains has shown that there is a high level of homogeneity between the various HBsAg sequences.
There are various anti-viral products on the market for the treatment of a chronic HBV infection. However, none of the available anti-viral drugs can clear infection; they only inhibit replication, thus, minimizing liver damage. Therefore, liver transplantation is the only treatment option for patients with HBV end-stage liver disease. HBV-diseased livers are estimated to represent 5% of all liver transplants in the United States while in China, around 85% of all liver transplantations are due to HBV infection.
To prevent re-infection of the new liver after liver transplantation, patients are currently treated with polyclonal HBV immunoglobulin (HBIg) combined with an antiviral agent. Polyclonal HBIg is prepared from pooled plasma from immunized donors and is also used as post exposure prophylaxis either as stand alone or in combination with a vaccine. HBIg preparations are indicated for the treatment of acute exposure to blood containing HBsAg, perinatal exposure of infants born to HBsAg-positive mothers, sexual exposure to HBsAg positive persons, and household exposure to persons with acute hepatitis B virus infection. Since there are some limitations associated with HBIg like availability, cost of goods, large injection volumes, adverse events, and the risk of blood-borne infection, there is a medical need for a monoclonal antibody product against HBV.
Several monoclonal antibodies against HBV have been described previously. PCT patent application PCT/IL97/00183 and PCT/IL97/00184, respectively, disclose human monoclonal antibody mAb 17.1.41 and mAb 19.79.5, against HBV surface antigen. These antibodies bind to various HBV subtypes. However, HBsAg of subtype adw2 (genotype C) is not recognized by the antibodies (Eren et al., 2000, Hepatology 32, 588). Genotype C is highly prevalent in China where the majority of chronically infected individuals reside.
PCT Patent Application WO2009069917 discloses a human antibody capable of neutralizing hepatitis B virus for the prevention and treatment of hepatitis B infection. It has not been demonstrated that this antibody binds to all major sero- and genotypes of HBV. In addition, none of the antibodies disclosed hitherto have been shown to neutralize the majority of commonly known vaccine-induced and anti-viral-induced escape mutants.
Thus, there is a need in the art for antibodies that bind and neutralize a large breadth of sero- and genotypes of HBV in addition to possible escape mutants and which can be manufactured on large industrial scale.